Dietary interactions with the bacterial sensing machinery ... · Nutrition, Faculty of Medical and...

REVIEW ARTICLEpublished: 04 April 2014

doi: 10.3389/fgene.2014.00064

Dietary interactions with the bacterial sensing machinery inthe intestine: the plant polyphenol caseNoha Ahmed Nasef, Sunali Mehta and Lynnette R. Ferguson*

Department of Nutrition, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand

Edited by:

Dimiter Dimitrov, Diavita Ltd., Bulgaria

Reviewed by:

Sander Kersten, WageningenUniversity, NetherlandsDimiter Dimitrov, Diavita Ltd., Bulgaria

*Correspondence:

Lynnette R. Ferguson, Department ofNutrition, Faculty of Medical andHealth Sciences, University ofAuckland, 85 Park Road, Grafton,Auckland 1023, New Zealande-mail: [email protected]

There are millions of microbes that live in the human gut. These are important in digestionas well as defense. The host immune system needs to be able to distinguish betweenthe harmless bacteria and pathogens. The initial interaction between bacteria and thehost happen through the pattern recognition receptors (PRRs). As these receptors arein direct contact with the external environment, this makes them important candidates forregulation by dietary components and therefore potential targets for therapy. In this review,we introduce some of the main PRRs including a cellular process known as autophagy, andhow they function. Additionally we review dietary phytochemicals from plants which arebelieved to be beneficial for humans. The purpose of this review was to give a betterunderstanding of how these components work in order to create better awareness onhow they could be explored in the future.

Keywords: microbiota, autophagy, phytochemicals,Toll-like receptors, Nod-like receptors

INTRODUCTIONThe human body is inhabited by complex communities ofmicroorganisms known as the microbiota which inhabit most sur-faces (Hooper et al., 2012). It is estimated that there is up to 100trillion (1014) bacteria (Savage, 1977; Ley et al., 2006; De Cruzet al., 2012) which is around 10-fold greater than the number ofhuman cells in the same individual (De Cruz et al., 2012). Themajority of the microbiota (10–100 trillion) inhabits the humangastrointestinal tract where they are most dense in the distal intes-tine (≥1012/cm3 intestinal contents). In the distal intestine themicrobiota has many beneficial functions such as fermentationof indigestible dietary residues, production of vitamin K, controlof intestinal epithelial cell (IEC) proliferation and differentiation,and the creation of a protective barrier against pathogens (Hooperet al., 2012).

In the intestine, a balance is required between the diges-tion of nutrients by symbiotic bacteria and protection againstpathogenic bacteria (Hooper et al., 2012). In healthy individ-uals, the intestinal immune system has evolved to distinguishbetween normal gut microbiota and pathogenic bacteria andresponds appropriately to each (Hooper et al., 2012). Duringbacterial infection, inflammation is activated as a defense mech-anism and is generally beneficial, However, if inflammationis uncontrolled, this can lead to chronic inflammation caus-ing disease such as inflammatory bowel disease (Medzhitov,2010). The appropriate response to the resident microbiota beginswith the microbiota sensing receptors which activates down-stream signals that respond by either defense, attach, repair, orprotection.

Studies have uncovered a mechanism that feeds into the bac-terial sensing pathway, known as autophagy (see Autophagy).Autophagy is a mechanism used by cells for degradation of cyto-plasmic material and is required for quality control and immuneregulation.

Current literature suggests that dietary components caninteract with processes in the host and has the potential tomodify its course. One of the best studied and largest groupof dietary components are phytochemicals. These compoundshave a wide range of effects that include anti-inflammatory, anti-cancer, anti-oxidant, and other beneficial properties both in vivoand in vitro. However, the results are controversial and some-times unclear. This is likely due to the differences in methodsused to assess polyphenols. These findings suggest that dietaryinterventions have the potential to modify and prime differentphysiological process including immunity. Understanding thesepathways further and how diet can interact with them will there-fore contribute to developing personalized nutrition to managedisease.

This review will focus on introducing the bacterial sensingmachinery and autophagy, and how they work. The second halfof this review will introduce plant polyphenols their digestion,metabolism, bioavailability, and how they interact with the hostcells to carry out their role.

BACTERIAL SENSINGThe innate immune system recognizes molecular structures thatare characteristics of microbial pathogens but not mammaliancells (Abbas et al., 2012). The microbial substances that stimu-late innate immunity are called pathogen-associated molecularpatterns (PAMPs). Different classes of microbes express differ-ent PAMPs. The innate immunity also recognizes endogenousmolecules that are produced by and released from damaged cells.These substances are known as damage-associated molecular pat-terns (DAMPs). Receptors that recognize PAMPs and DAMPs areexpressed on phagocytes that include macrophages, neutrophils,dendritic cells (DCs), and epithelial cells that compose the bar-rier interface between the body and the external environment(Figure 1). These receptors are known as pattern recognition

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Ahmed Nasef et al. Dietary interactions with colonic bacteria

FIGURE 1 | Host cells including epithelial cells, macrophages, and dendritic cells contain pattern recognition receptors (PRRs) that can recognize

molecules released from pathogens during infection (PAMPs) or stressed cells during tissue damage (DAMPs). This activates downstream pathways toresolve infection or repair damaged tissue.

receptors (PRRs). When molecules bind to PRRs, they activate sig-nal transduction events that promote the anti-microbial and pro-inflammatory functions of the cells in which they are expressed(Abbas et al., 2012).

There are several families of PRRs that have been identified(Abbas et al., 2012). These include the Toll-like receptors (TLRs),Nod-like receptors (NLRs), RIG-like receptors, and other cell-associated PRRs (Abbas et al., 2012). The most widely studiedPRRs are the TLRs and NLRs which will be discussed in detailin this section.

Toll-LIKE RECEPTORSToll-like receptors are a family of transmembrane proteins thatrecognize and respond to: (1) PAMPs (Ozinsky et al., 2000), (2)DAMPs (Piccinini and Midwood, 2010), and (3) pathogenic andnon-pathogenic microorganisms in the form of microorganism-associated molecular patterns (MAMPs; Ramos et al., 2004). Todate, a total of 10 TLRs have been identified in humans (TLR1–10;Abreu, 2010).

Toll-like receptors are predominantly expressed on host innateimmune cells including epithelial cells (Abreu, 2010). The TLRs arecomprised of type I transmembrane glycoproteins expressed onthe cell surface (TLR1, TLR2, TLR4–6, and TLR10) or endosomalcompartments (TLR3, TLR7–9). All TLRs express the N-terminalectodomain that contains leucine rich repeats (LRRs) involved inligand recognition and co-receptor interaction. They also expressa transmembrane region and an intracellular region containinga Toll/IL1R resistance (TIR) signaling domain (Singletary andMilner, 2008).

Each TLR recognizes specific molecules that activate it. TLR4is the main receptor for lipopolysaccharides (LPSs) from Gram-negative bacteria. TLR4 can also sense mannan which is the fusion(F) protein of respiratory syncytial virus (RSV) and Chlamydialheat shock protein (hsp). TLR2 interacts with TLR1 or TLR6to recognize tri- or diacylated lipoproteins from Gram-positivebacteria, mycobacteria, or mycoplasma (Lien et al., 1999). TLR5detects bacterial flagellin (Gewirtz et al., 2001; Mizel and Snipes,2002). Endosomal TLRs sense viral double stranded RNA (TLR3;Alexopoulou et al., 2001), single strand RNA (TLR7 and TLR8;Diebold et al., 2004; Heil et al., 2004), and hypomethylated CpGmotifs present in bacterial, viral, and fungal DNA (TLR9; Beutler,2008).

Most TLRs form homodimers upon ligand binding. In con-trast, TLR2 forms heterodimers with either TLR1 (TLR1/2) orTLR6 (TLR2/6) to respond to tri- and diacylated lipoproteins,respectively (Schenk et al., 2009). Gram-positive bacteria andmycobacteria express diacylated lipoproteins, whereas lipopro-teins of Gram-negative bacteria have an additional acyl group.This puts TLR2 in a unique position of being capable of respond-ing to lipoproteins from wide range of bacteria making it a vitalbacterial sensing cell surface receptor against infection (Schenket al., 2009).

Toll-like receptor response to molecules can be divided into twodistinct intracellular pathways (Smoak et al., 2010): one leading tothe activation of the MyD88-dependent pathway and the otherthrough the TIR-domain-containing adapter-inducing interferon(IFN)-β (TRIF) signaling arm (Covert et al., 2005). All TLRs (withthe exception of TLR3) use the MyD88 signaling pathway which

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associates with the TLRs through the TIR–TIR domain inter-actions (Beutler, 2008). This is followed by the recruitment ofIL1R-associated kinase 4 and kinase 1 which signals downstreamto activate nuclear factor kappa beta (NFκβ), mitogen-activatedprotein kinases (MAPKs), and inflammatory cytokines (Doyleand O’Neill, 2006). TLR3 solely engages with TRIF to activateinflammatory cytokines and type I IFNs. On the other hand, TLR4which uses both MyD88- and TRIF-dependent pathway, also usesTRIF to signal expression of co-stimulatory molecules and type1 IFNs via the activation of TANK-binding kinase 1 (TBK1) andIFN regulatory factor (IRF) 3 and 7 (Doyle and O’Neill, 2006;Beutler, 2008). TLR4 and TLR2 require the bridging adaptor TIRdomain-containing adapter protein (TIRAP) to recruit MyD88 tothe TLRs. However, TLR4 also requires a bridging adaptor TRIF-related adapter molecule (TRAM) that recruits TRIF to the TLR4complex (Yamamoto et al., 2003). TLR4 which recognizes Gram-negative bacteria, mainly LPS, represents the principal pathwayresponsible for detecting and responding to endotoxins, resultingin the triggering of both the MyD88-dependent and -independentpathways (Fukata et al., 2009). Sensing of conserved PAMPs suchas LPS via the LRR-containing ectodomain leads to TLR dimer-ization. This brings their TIR signaling domain closer to eachother which form an intracellular docking platform that enablesrecruitment of adaptor proteins and kinases (Beutler, 2008). Inone study, delayed activation of NFκβ in MyD88-deficient mouseembryo fibroblast (MEF) model cells as compared to the wildtype cells was reported, suggesting that although both pathwaysactivate NFκβ and inflammation, the TRIF-dependent pathwaycan do this with delayed kinetics (Covert et al., 2005). The studyfound that LPS-stimulated MyD88-deficient cells, in comparisonwith cells containing MyD88- and TRIF-deficient cells showedsubstantially slower kinetics to reach the initial peak for NFκβ

activation. They also found the NFκβ activation in MEF cellswith TRIF began much earlier after stimulation with LPS thanin MEF cells deficient in TRIF. The MEF cells with and with-out MyD88 sustained the activation of the NFκβ levels for muchlonger than TRIF-deficient MEFs. These observations suggest that,while the dependent pathway triggers the response to the initialstimuli, the independent pathway is responsible for the suste-nance of the pro-inflammatory program (Biswas and Tergaonkar,2007).

In one study, TLR2 was also shown to activate a second path-way in parallel to MyD88-dependant pathway (Cario et al., 2007).The authors found that TLR2 signaling involves the PI3K–Aktpathway which modulated intestinal epithelial barrier functionin vitro in IECs and ex vivo in mice. Stimulating TLR2 withthe synthetic triacylated lipopeptide analog Pam3CSK4 in IEC,resulted in MyD88-dependant phosphorylation of the Akt p70S6KS6 ribosomal pathway through the PI3K pathway. In contraststimulation with LPS did not lead to phosphorylation of Aktand its downstream substrates above baseline IEC. In their studythey also found that TLR2 functions through the PI3K–Akt toattenuate the MAPK–NFκβ-signaling cascade. Overexpression ofAkt leads to the significant dampening of PAM3CSK4-inducedNFκβ activation in vitro. Their findings suggest that the PI3K–Akt secondary pathway ensures tolerance toward ligands fromcommensal bacteria (Cario et al., 2007). This study looked at

PAM3CSK4 which activates TLR2/TLR1. Whether the sameresults apply to the activation of TLR2/TLR6 remains to beinvestigated.

Nod-LIKE RECEPTORSWhen pathogens enter the cytosol of cells they are detectedby cytosolic receptors known as NLRs which elicit the appro-priate response to clear or control the infection (Correa et al.,2012). They do so by recruiting a number of molecules to forma complex multi-protein structure referred to as the inflam-masome (or a signalosome in the case of NOD1 and NOD2;Correa et al., 2012).

Structure of the NLRs and intracellular signaling via the NLRsAll NLR proteins contain: a C-terminal region characterized bya series of LRR domains that are involved in recognizing micro-bial components or ligands; a central nucleotide domain termedthe NACHT domain that is important for self-oligomerization;and a N-terminal effector domain that is responsible for theinteraction of the NLR with downstream signaling molecules(Correa et al., 2012). NLRs can vary in the number of LRRsas well as their N-terminal interacting domain. Many NLRshave been identified that include NOD1, NOD2, NLRP1,NLRP3, NLRP6, NLRP7, NLRC4, NAIP5, AIM2, and RIG-I(Chen et al., 2009).

Based on NLR’s N-terminal protein–protein interacting mod-ule, the NLRs can be divided into three subgroups depending onthe interacting domain they have (Correa et al., 2012): (1) cas-pase recruitment domains (CARDs), (2) pyrin domains (PYDs),or (3) other domains such as baculovirus IAP (inhibitor of apop-tosis) repeat domains (BIRs). The type of interacting domain thatan NLR possess will determine the type of multiprotein complexrecruited and the type of response achieved.

When the NOD receptors are activated by their ligands,the receptors oligomerize through mediation via the NACHTdomains (Correa et al., 2012). This recruits RIP2 (receptor inter-acting protein 2) domain where the CARD of NOD1 or NOD2bind the CARD of RIP2. This results in the ubiquitinationby IAPs and recruitment of the linear ubiquitin chain assem-bly complex (LUBAC) by the X-linked inhibitor of apoptosisprotein (XIAP) with further binding of TAB/TAK1 complex.TAK is an upstream activator of the IκB kinase (IKK) com-plex as well as the stress kinase cascades that results in JNKand p38 MAPK activation (Correa et al., 2012). In addition,NOD1 and NOD2 have been reported to interact with otherNLRs that are important for caspase-1 activation (Correa et al.,2012). Most NLRs (with the exception of NOD1 and NOD2)will recruit caspase-1 either directly or indirectly (Correa et al.,2012). Caspase-1 processes a number of cellular substrates whichincludes the conversion of pro-IL1β and pro-IL18 into their activeforms (Martinon et al., 2009). In addition to pro-inflammatoryeffect, continuous activation of caspase-1 can result in a formof cell death known as pyroptosis. This has characteristics ofboth apoptosis and necrosis (Martinon et al., 2009). NOD2was shown to specifically and directly interact with NLRP1,NLRP3, and NLRP12, whereas NOD1 interacts only with NLRP3(Moreira and Zamboni, 2012).





NOD1 and NOD2NOD1 and NOD2 are the first NLRs that were identified andare examples of NLRs containing a CARD (Inohara et al., 1999;Ogura et al., 2001). NOD1 has been widely expressed in manycell types and tissues in vivo, whereas NOD2 has been found inmacrophages, DCs, paneth cells, keratinocytes, intestinal epithe-lium, lung oral cavity, and osteoblasts. Both proteins are activatedby bacterial peptidoglycan (PG; Schleifer and Kandler, 1972). PGis responsible for providing shape and mechanical rigidity to bac-teria (Schleifer and Kandler, 1972). It is a major component ofGram-positive bacterial cell wall, while in Gram-negative bacte-ria it is found as a thin layer in the periplasmic space (Correaet al., 2012). NOD2 is a general bacterial sensor that detects anddirectly binds muramyl dipeptide (MDP) a motif that is presentin the PGs of both Gram-positive and -negative bacteria (Girardinet al., 2003b). In contrast NOD1 is dependent on the presenceof L-Ala-y-D-Glu-diaminopimelic acid (m-DAP), an amino acidcharacteristic of most Gram-negative and some Gram-positivebacteria (Girardin et al., 2003a). Several groups have reported arole of NOD1 in the detection of a variety of invasive Gram-negative bacteria such as E. coli (Kim et al., 2004) and Chlamydia(Opitz et al., 2005). Because PG from both Gram-positive and

-negative bacteria contains MDP, NOD2 functions as a gen-eral sensor of most bacteria (Correa et al., 2012). However PGfrom Gram-positive bacteria do not contain m-DAP (with a fewexceptions), NOD1 mainly senses products from Gram-negativebacteria (Correa et al., 2012). Moreover, several studies havedemonstrated the activation of other NLRs including NLRP3 andNLRP1 by MDP (Moreira and Zamboni, 2012). The activationof these NLRs with MDP leads to the secretion of ILβ (Martinonet al., 2007).

AUTOPHAGYAutophagy is derived from the Greek word for “self-eating,” andrefers to the process by which the cells breakdown and reuse theirown constituents (Levine et al., 2011). Unlike proteasomes thatare also involved in cellular degradation, autophagy is a recy-cling pathway and plays an important role in maintaining cellularhomeostasis (Singletary and Milner, 2008). Autophagy can bebroadly divided into three types based on the method of trans-fer used to deliver the cellular content into the lysosome (Cuervoand Macian, 2012). The three types of autophagy are macroau-tophagy, microautophagy, and chaperone-mediated autophagy(Figure 2; Cuervo and Macian, 2012). However, the different types

FIGURE 2 | Microautophagy occurs when bulk cytosolic components are

directly engulfed by lysosomes through the invaginations of the

lysosomal membrane where they are rapidly degraded by hydrolase

enzymes. This process has been studied in yeast and is still poorlycharacterized in mammals (Cuervo and Macian, 2012). Chaperone-mediatedautophagy (CMA) is a very complex and specific pathway which is initiatedwhen a chaperone recognizes a targeting motif in the cytosolic protein to bedegraded. The chaperone/substrate complex reaches the lysosome and the

substrate is internalized through the translocation complex in the lysosomalmembrane (Cuervo and Macian, 2012). CMA is considerably different fromthe other types of autophagy because it does not directly engulf the proteinmaterial but selectively transfers it individually into the lysosome (Kadian andGarg, 2012). The most extensively described type of autophagy in theliterature is macroautophagy which is also referred to as autophagy in theliterature. A review on macroautophagy (which will be referred to asautophagy from this point) is provided in this review.





of autophagy do not function in isolation but often function in aninterconnected manner.

Autophagy is the main pathway that is activated in response toa number of stressors with a pro-survival function (Cuervo andMacian, 2012). In addition, some level of the basal autophagyexists in almost all cell types and contributes to maintenance ofcellular homeostasis (Deretic, 2011). Autophagy either degradesor recycles the cytoplasmic content initially by the formation of anautophagosome. Autophagosomes are intermediate membrane-surrounded structures that perform two major functions: firstlyit isolates the targeted cytoplasmic content within a cell from theremaining cellular matter; secondly it delivers the isolated cyto-plasmic content into mammalian lysosomes or plant and yeastvacuoles. There are different types of selective autophagy that havebeen described according to the substrate they target (Lapaque-tte et al., 2012). Aggrephagy refers to degradation of aggregatedproteins (Rubinsztein, 2006), pexophagy to peroxisome degrada-tion (Iwata et al., 2006), mitophagy to mitochondria degradation(Okamoto et al., 2009), reticulophagy to ER degradation (Bernaleset al., 2006), and xenophagy to the degradation of intracellularmicroorganisms (Deretic, 2010).

MECHANISM OF AUTOPHAGYAutophagy can be induced by a variety of immune signals andstress stimuli, including inflammatory cytokines, starvation andenergy stress, ER stress, PAMPs and DAMPs, hypoxia, redox stress,and mitochondrial damage (Kroemer et al., 2010). Steps involvedin the process of autophagy after initiation are summarized asfollows:

Upon initiation, autophagy formation goes through severalsteps (Kroemer et al., 2010). Beclin 1 (Atg6 in yeast), UVRAG(Vps38 in yeast), Vps34 (Class III PI3K), and Vps15 are assembledto form the lipid kinase signaling complex to mediate nucleationor vesicle formation. The molecules to be digested are surroundedby the isolating membrane called the phagophore which startsto elongate (Kroemer et al., 2010). There are two ubiquitin-likeconjugation systems which are part of the membrane elonga-tion process (Kroemer et al., 2010). The first system involves thecovalent conjugation of Atg12 to Atg5 with the help of Atg7.This results in the association of Atg16L1, forming the Atg16L1–Atg12–Atg5 complex. This complex functions by recruiting thelipidated form of the microtubule-associated protein 1 light chain3 (LC3-II/Atg8 in yeast; Yang and Klionsky, 2010). Small frac-tions of the cytosolic ATG12–ATG5–ATG16L1 complex associatewith the outer membrane of the phagophore and dissociate fromit on or near completion of the double-membrane autophago-some (Mizushima et al., 2003). Atg5 and Atg16L1 depend on eachother for their membrane targeting; whereas Atg12 is dispens-able for Atg5–Atg16L1 membrane association (Mizushima et al.,2003).

The second system that is important in the elongation pro-cess involves the actual lipidation of LC3. This is done by theconjugation of phosphatidylethanolamine (PE) to the glycineresidue of the mammalian LC3 by the sequential action of Atg4,Atg7, and Atg3 (Yang and Klionsky, 2010). LC3 is initially syn-thesized as its unprocessed form proLC3. LC3 is cleaved at itsC-terminus by the cystine protease Atg4 into the mature form

LC3-I. LC3-I is conjugated to PE by the ubiquitin E1-like pro-tein – Atg7, and the ubiquitin E2-like protein – Atg3, to generatea smaller lipidated form of LC3, LC3-II. This lipid conjugationresults in the conversion of the soluble form of LC3 (knownas LC3-I) to its membrane form LC3-II. LC3-II is stably asso-ciated with the autophagosome membrane. Atg16L1 determinesthe site of LC3 attachment through an interaction with Golgi-resident small GTPase Rab33 (Itoh et al., 2008). LC3-II is foundboth on the luminal and cytosolic surfaces of autophagosomes.Elongation is then followed by the closure of the autophago-some and fusion with the lysosomal compartment and thehydrolysis of the molecules within the autophagosome (Tanida,2011).

DIETARY PHYTOCHEMICALSPlant secondary metabolites also known as phytochemicals arederived from the products of primary metabolism in plants. Theyare defined as bioactive non-nutrient plant compounds foundin fruits, vegetables, grains, and other plant foods (Liu, 2012).It is estimated that there have been more than 5,000 individ-ual phytochemicals identified so far. However, a large percentageremains undiscovered (Shahidi and Naczk, 1995). According to theliterature, phytochemicals have been classified broadly into phe-nolic compounds, terpenoids, nitrogen-containing compounds,alkaloids and sulfur-containing compounds, phytosterols, andcarotenoids (Table 1; Rein et al., 2013).

Phytochemicals have a wide range of molecules, starting fromthe low-molecular weight phenolic acids to the highly polymer-ized proanthocyanidins. In addition to their broad classification,phytochemicals have been divided into two distinct classes: watersoluble and lipid soluble (Neilson and Ferruzzi, 2012).

Unlike vitamins and minerals, these phytochemicals are notrecognized as essential dietary components because lacking inthem does not cause any specific deficiency. However, thesebioactive compounds have been linked to biological activityin mammalian systems that may impact health and diseaserisk (Liu, 2012). Most dietary phytochemicals are considerednon-essential nutrients. Therefore they are defined as com-pounds that can be found in the organism, but not made bythe organism and not expected to be present in the organ-ism, or used for normal metabolic function (also known asxenobiotics; Neilson and Ferruzzi, 2012). Many foods containhundreds or even thousands of phytochemicals with variableand mostly unknown biological activity (Neilson and Ferruzzi,2012). Of these, the polyphenols and the carotenoids are the bestunderstood.

Phytochemicals vary widely in their composition in fruits andvegetables, nuts, and grains. This variation depends on severalfactors including soil (Price et al., 1989; Mansfield et al., 1999), cli-matic conditions (Albert et al., 2009), agricultural methods (Binnset al., 2002), physiological stress under which plants are grown(Gershenzon, 1984), degree of ripeness (Faurobert et al., 2007),storage conditions and length of storage before consumption (Liu,2012). Thus no single value is representative of the amount of phy-tochemicals found in an individual plant species. The mechanismof action of different phytochemicals are often complimentary toone another and are likely to work synergistically (Liu, 2012).





Table 1 |The different classes of phytochemicals.

Phytochemical class Description Reference

Phenolic compounds At least one aromatic ring; one or more hydroxyl groups attached; more than 8000 structures;

includes flavonoids and phenolic acids

Tsao (2010)

Terpenoids Sometimes called isoprenoids; derived from five carbon isoprene units; more than 40,000

molecules; contributes to the aroma and flavor of plants

Aharoni et al. (2005)

Nitrogen-containing alkaloids Low molecular weight, nitrogen-containing compounds; mostly derived from amino acids;

found in ∼20% of plant species; exploited as pharmaceuticals, stimulants, narcotics, and

poisons

Wink (1998)

Sulfur-containing compounds Glucosinolates in cruciferous crops (e.g., Broccoli); Alliins in Allium crops (e.g., Garlic);

compartmentalized enzyme–substrate systems that produce a variety of products when the

plant tissue is damaged

Mithen (2008)

Phytosterols Plant steroids equivalent to cholesterol in animals; found mainly in vegetable oil Ling and Jones (1995)

Carotenoids Widely spread in plants; provides the colors yellow, red, and orange to plants; 600 known

species; all contain eight isoprenes molecules; 40 carbon atoms

Kadian and Garg (2012)

Like other xenobiotics, phytochemicals are subjected to thebody’s detoxification system (Neilson and Ferruzzi, 2012). Thissystem is designed to reduce the toxicity of potentially toxiccompounds. Biotransformation of xenobiotics is catalyzed byenzymes known as drug-metabolizing enzymes to enable theirmetabolism, detoxification and excretion from the body (Yanget al., 2010). The drug-metabolizing enzymes can be broadly clas-sified into three groups where phase I and phase II are enzymeswhile phase III are transporters.

PHASE I METABOLISMMetabolism usually begins with the hydrolysis of polymeric,glycosylated and/esterified native compounds via the brush bor-der of the small intestine, and the microbial enzymes (phaseI metabolism; Spencer et al., 1999). Phytochemicals are usuallypresent in food as glycosides or other conjugates and need to behydrolyzed in order to be absorbed (Yang et al., 2010). Phase Imetabolism encompasses both redox and hydrolytic reactions. Theoxidation of xenobiotics in the intestine is mainly performed by adiverse family of enzymes referred to as cytochrome p450 or CYPs(Yang et al., 2010).

PHASE II METABOLISMOnce absorbed into the IECs called enterocytes, xenobiotics aresubjected to phase II metabolism by the process of conjugation(Yang et al., 2010; Neilson and Ferruzzi, 2012). Conjugation isa common detoxification reaction which reduces the number ofreactive hydroxyl groups on the compound and includes glu-curonidation, sulfation, methylation, acetylation, glutathione, andamino acid conjugation (Jancova et al., 2010). The process ofconjugation makes the xenobiotics more polar and hydrophilicresulting in increased solubility which is necessary for urinaryexcretion (Dutton, 1978). This involves conjugation reactionswhere a hydroxyl group on a compound is modified by the addi-tion of sulfate, glucoronic acid, or methyl group (Neilson andFerruzzi, 2012).

Phase II drug metabolizing enzymes are mostly belong-ing to a group of enzymes known as transferases that cat-alyze the transfer of functional groups. These include UDP-glucuronosyltransferases (UGTs), sulfotransferases (SULTs), N-acetyltransferases (NATs), glutathione S-transferases (GSTs), andvarious methyltransferases [mainly thiopurine S-methyl trans-ferase (TPMT) and catechol O-methyl transferase (COMT);Jancova et al., 2010]. UGT isoforms have a broad tissue distri-bution with a major location in the liver and the small intestine(Strassburg et al., 2000; Izukawa et al., 2009). The SULT fam-ily have been identified as either cytosolic or membrane boundand exhibit a wide distribution including the liver, brain, breast,intestine, jejunum, lung, adrenal glands, endometrium, placenta,kidney, and blood platelets (Riches et al., 2009). NATs are cytosolicenzymes found in many tissues (Windmill et al., 2000). SolubleGST is widely distributed around the body and has been found inthe liver, kidney, brain, pancreas, testis, heart, lung, small intestine,skeletal muscles, prostate, and spleen (Whalen and Boyer, 1998).TPMT is a cytosolic enzyme and mainly found in the liver andkidney with low levels in the brain and lungs (Pacifici et al., 1991).COMT is an intracellular enzyme and is either a cytoplasmic sol-uble form or a membrane bound form located in the cytosolicside of the rough endoplasmic reticulum (Jeffery and Roth, 1984).COMT is expressed in most tissues with the highest expressionin the liver, kidney, intestine, and brain (Nissinen et al., 1988;Boudíková et al., 1990; Hong et al., 1998).

The metabolites after phase II metabolism appear to be effi-ciently effluxed by the efflux transporters in phase III metabolism(Neilson and Ferruzzi, 2012).

PHASE III METABOLISMIn phase III metabolism, the metabolites are either effluxed backinto the intestinal lumen or to the bloodstream from where it istaken to the liver. Enterocytes are intestinal cells which act as thefirst barrier against xenobiotics. These cells use the action of effluxtransporters to prevent the buildup of xenobiotic compounds in





their cytoplasm. The transporters either returns the compounds(either in its native form or metabolized form) back into the lumenor transport them to the portal vein where they enter the liver forfurther processing (Neilson and Ferruzzi, 2012).

The efflux of phytochemicals is mediated by a number oftransporters. The efflux of polyphenols has been shown to befacilitated by the ATP-binding cassette (ABC) superfamily of trans-membrane transporters, which is termed phase III metabolism(Wakabayashi et al., 2006; Planas et al., 2012). Multidrug resis-tant protein (MRP) 2 is an apical/luminal end transporter thatwas shown to efflux the compounds back to the lumen (Lambertet al., 2007). MRP1 is a basolateral/blood stream end trans-porter that transport the compounds to the blood circulation(Lambert et al., 2007).

BIOAVAILABILITY OF DIGESTED COMPOUNDSThe rate and extent to which the active compound is absorbedfrom its ingested form and becomes available at the site of actionis defined as bioavailability (Neilson and Ferruzzi, 2012). Thisdefinition takes into account two factors in vivo: (1) the activecompound must be present at the site of action to produce itsbiological activity and (2) the concentration of the compoundat the site (Neilson and Ferruzzi, 2012). This definition is moreeasily applicable to pharmaceuticals than to dietary phytochem-icals originating from complex food matrices. Bioavailability ofdietary phytochemicals is not only complicated by the biochem-ical properties of the molecule but also because of enzyme andmicrobial-mediated metabolism and active efflux (Neilson andFerruzzi, 2012).

INTESTINAL EPITHELIAL CELLSIntestinal epithelial cells have many functions apart from absorp-tion. They are involved in the metabolism of food substances andalso intestinal immunity. One interesting characteristic uniqueto IEC is that they are usually exposed to high concentrations ofnutrients, non-nutrients, microbes, and xenobiotics. This suggeststhat the IEC’s function is affected or even regulated by exter-nal substances including food components despite their functionbeing generally controlled by internal factors such as hormonesand cytokines (Shimizu, 2010).

Several studies indicate that the small intestine has poor absorp-tion of dietary polyphenols (Manach et al., 2005). Therefore mostof the ingested dose passes through the small intestine and reachesthe colon. The colon is home to a complex bacterial communitythat has the ability to extensively ferment unabsorbed material(van Duynhoven et al., 2011; Neilson and Ferruzzi, 2012).

PLANT POLYPHENOLSPolyphenols are a large structurally diverse group of organic com-pounds that contain at least one aromatic ring with one or morehydroxyl groups attached (Rein et al., 2013). Plant foods containmany different types of polyphenols, which are increasingly seenas effective protective agents against disease (Scalbert et al., 2002,2005; Shapiro et al., 2007; Priego et al., 2008; Bravo, 2009; DelRio et al., 2010; Sies, 2010; Gonzalez et al., 2011). Polyphenolsrepresent a wide range of compounds which are divided into sev-eral classes determined by their structure. These include phenolic

acids, flavonoids, still beans, and ligands (Del Rio et al., 2010). Inthis section, plant polyphenols will be reviewed in detail.

Absorption of polyphenolsPolyphenols ingested from food remain outside the body untilthey are absorbed through epithelial cells lining the gastrointesti-nal tract (Neilson and Ferruzzi, 2012). Most intact polyphenolabsorption happens in the small intestine with further absorp-tion occurring in the colon of the large intestine (Scalbert et al.,2002). In order to be absorbed by the epithelial cells in the gutseveral factors need to take place. First, polyphenols must bereleased from any interactions with other food components (Neil-son and Ferruzzi, 2012). This is done by mechanical action suchas chewing and grinding in the mouth. Further breakdown hap-pens in the stomach via the gastric juices (Neilson and Ferruzzi,2012). Second, the stability of the polyphenols in the intestine willgreatly impact the concentration reaching the epithelial surface.Third polyphenols must be soluble in the bulk aqueous phase ofthe gastrointestinal milieu in order to facilitate diffusion throughthe unstirred water layer that protects the epithelial surface layer(Neilson et al., 2009).

According to Lipinski’s Rule of 5, compounds that have fiveor more hydrogen bond donors (OH and NH groups), 10 ormore hydrogen bond acceptors (notably N and O), a molecularweight of greater than 500, and a log P greater than 5 are usuallypoorly absorbed after oral administration. This is because of theirlarge actual size (high molecular weight), high polarity or largeapparent size (due to the formation of a large hydration shell;Yang et al., 2008). Dietary polyphenols range from species thatviolate the Lipinski’s rule and as such have been shown to havepoor bioavailability (Lipinski et al., 2001; Mulder et al., 2001; Yanget al., 2008), while others have been shown to have good absorp-tive characteristics as predicted by the Lipinski’s rules (Yang et al.,2008).

It is believed that the absorptions of polyphenols intothe epithelial cells of the small intestine (enterocytes) occursthrough both active and passive diffusions (Crespy et al., 2003;Vaidyanathan and Walle, 2003; Lambert et al., 2007; Neilson andFerruzzi, 2012). Polyphenols appear to compete for the monocar-boxylic acid transporter (Bravo, 2009). Passive diffusion appearsto contribute to the absorption of flavonoids with high log P valuessuch as isoflavones and flavonones but it contributes little to thosewith a low log P value such as flavan3-ols (Neilson and Ferruzzi,2012).

FlavonoidsFlavonoids are the largest class of plant polyphenols present infruits and vegetables. There are more than 4,000 distinct flavonoidsidentified to date (Shahidi and Naczk, 1995). The main subclassesof flavonoids common in diet are flavones (e.g., luteolin and api-genin), flavonols (e.g., quercetin, kaempferol, and myricetin),flavon-3-ols (catechin, epicatchin, epigallocatechin, epicatechingallate, and apigallocatechin gallate), isoflavones (e.g., genisteinand daidzein), flavonones (e.g., naringenin), and anthocyanidins(e.g., cyaniding and malvidin; Liu, 2012). This class of polyphe-nols has received attention due to their potent anti-oxidant activity(Rice-Evans et al., 1995) and possible role in the prevention of





cancer (Birt et al., 2001), cardiovascular (Hooper et al., 2008),neurodegenerative (Nakajima et al., 2007), and infectious diseases(Shin et al., 2005).

Flavonoids are often recognized as xenobiotics by the intesti-nal detoxification system (Jeong et al., 2005). They are oxidized byphase I enzymes, conjugated by phase II enzymes and then excretedfrom the cells by phase III transporters (Shimizu, 2010). Recentstudies have observed that the detoxification enzymes are regu-lated by a variety of transcription factors and regulatory proteins(Kusano et al., 2008).

With the exception of catechins (which have a notable pres-ence in tea and are also found in fruits), flavonoids in natureare almost always found as a glycoside, i.e., attached to a sugargroup (Aherne and O’Brien, 2002). The aglycone, which is theflavonoid without the sugar, is not normally found in food; how-ever, the processing of plant food such as fermentation can increasethe level of aglycone such as in the case of miso soup. Glyco-sylation increases the polarity of flavonoids which is importantfor storage in the plant cell vacuoles. Flavonols and flavonesoccur in food usually as o-b-glycosides (Aherne and O’Brien,2002). Of the major flavonoid classes, the flavonols predomi-nate in fruits in which a variety of glycosides have been identified,whereas in vegetables quercetin glycosides predominate (Aherneand O’Brien, 2002). When glycosides are formed, the preferredglycosylation site on the flavonol molecule is the C-3 position andless frequently the C-1 position (Aherne and O’Brien, 2002). D-glucose is the most usual sugar residue but other carbohydratesubstitutions include arabinose, galactose, glucorhamnose, lignin,I-rhamnose, and xylose 4 (Aherne and O’Brien, 2002). For exam-ple, quercetin can be linked to the 3-o-glycoside rhamnose toyield quercitrin, or glucorhamnose to yield rutin (Aherne andO’Brien, 2002). Flavonols are found in nearly all fruits and vegeta-bles with quercetin glycosides being the most abundant in the diet(Psahoulia et al., 2007).

Polyphenols in health and diseaseCross-sectional and prospective epidemiologic studies have foundan association with diets rich in plant foods and protection againstdegenerative diseases such as cancer and cardiovascular diseases(CVDs; Hertog et al., 1993b; Omenn et al., 1996; Liu et al., 2005;Scalbert et al., 2005; Kuriyama et al., 2006; Del Rio et al., 2010;Sies, 2010). Intervention studies in humans and animals have con-tributed further evidence supporting polyphenolic modulation ofvascular and platelet function, blood pressure (Hodgson and Croft,2006), and improved plasma lipid profile (Scalbert et al., 2005). Areview analyzed 200 studies on the relationship between intake offruits and vegetables and different types of cancers (Block et al.,1992). In 128 of the 156 dietary studies, the consumption of fruitand vegetables was reported to be significantly protective. The riskof cancer was twofold higher in those individuals that had rela-tively low fruit and vegetable intake (Block et al., 1992). Severalepidemiological studies have examined the role of phytochemicalson CVD prevention. Dietary flavonoid intake was significantlylinked to reduced heart disease in general as well as coronary heartdisease specifically related mortality (Hertog et al., 1993a, 1995).

There have been several in vivo studies with polyphenols(reviewed by Gonzalez et al., 2011). These studies have indicated

that polyphenols help in the regulation of diseases includingimmunoregulation, estrogen modulation, and protease inhibi-tion in rheumatoid arthritis; immunoregulation in experimentalallergic encephalomyelitis (a model for multiple sclerosis); anti-inflammatory effects in inflammatory bowel disease; anti-allergiceffects in asthma; anti-inflammatory and anti-oxidant effect,transcription factor regulation, and protective mechanisms inatherosclerosis; anti-inflammatory and protection against tissuedamage in ischemia-reperfusion; anti-inflammatory and anti-oxidant effects and control of hyperinsulinemia, hypertension,dyslipidemia in metabolic syndrome, and skin inflammation(Gonzalez et al., 2011).

There have been several in vitro studies related to the anti-inflammatory, anti-oxidant, and immunomodulatory actions ofpolyphenol and in particular flavonoids (reviewed by Gonzalezet al., 2011). The phytochemical chlorogenic acid (found in manyagricultural products such as coffee and apples) and its metabolitecaffeic acid have been shown to reduce the secretion of the proin-flammatory cytokine IL8 in the human IECs caco2, when theywere stimulated with TNFα and H2O2 (Zhao et al., 2008). Similarresults were found for isoflavone fractions in another study (Satsuet al., 2009). Chlorogenic acid was also observed to inhibit LPSinduced cyclooxygenase-2 expression in mouse macrophage cells,by suppressing NFκβ activation (Shan et al., 2009).

In vitro studies have also shown that dietary substances includ-ing polyphenols, can be modulators of tight junctions in theintestinal epithelium (Suzuki et al., 2011; Kosiñska and And-lauer, 2013). In addition, polyphenols have been reported tomodulate transporter function. A study reported that glucoseabsorption via the intestinal SGLT1 was slightly inhibited in ratsby hydrolyzed metabolites from gymnemic acid extracted fromGymnema sylvestre leaves (Yoshikawa et al., 1997). Another studylooked at the effect of polyphenols from Cocoa on T84 colonicepithelia in Ussing chambers on the forskolin-stimulated cysticfibrosis transmembrane conductance regulator (CFTR; Schuieret al., 2005). CFTR is the major chloride ion channel in the apicalmembrane of the epithelia and it is critically involved in salt andwater secretion and absorption in the gastrointestinal tract andother epithelial membranes. Pharmacologic blocking of CFTR isthought to inhibit salt and water loss during diarrhea. They foundthat cocoa flavonols act as a mild CFTR blocker. The authorsnoted that flavonols are poorly absorbed in the small intestine andtherefore large amounts of the compound would be present inthe intestinal lumen to interact with the apical surface of the IECs(Schuier et al., 2005).

In vitro studies have also highlighted that phytochemicals mayhave detoxification properties. pregnane X receptor (PXR) isinvolved in the recognition of xenobiotics and upregulation ofthe detoxification enzymes which help in metabolizing harmfulcompounds and excreting them (Shimizu, 2010). A study lookedat the effect of food substances on PXR-mediated regulation of thedetoxification enzymes using human intestinal LS180 cells (Satsuet al., 2008). Of the 42 phytochemicals tested, three flavonoids andtwo terpenoids activated PXR-dependent transcriptional activitysuggesting that these compounds activate the intestinal detoxifica-tion system and are involved in the barrier function against toxicchemicals (Satsu et al., 2008; Shimizu, 2010). In addition, food





substances have also been shown to bind toxin directly, interferingwith their absorption through the intestine (Natsume et al., 2005).These studies suggest that phytochemicals are not only processedby the epithelium but also influence and modulate it.

One study has investigated the anti-oxidant capacity of intactjuice blend in both in vivo and in vitro models (Jensen et al.,2008). The authors initially established that their juice blendto contained major polyphenol compounds including antho-cyanins, proanthocyanidins, and phenolic acids. Using a CAP-eassay they established that their juice blend is able to provideanti-oxidant protection in vitro. They also found that ROS pro-ductions were reduced in polymorphonuclear leukocytes cells invitro after incubation with the juice blend. They then went onto testing the juice blend in vivo using a randomized, placebo-controlled trial using 12 individuals in a within subject design.Using the CAP-e assay they observed that there is an increase inanti-oxidant capacity within 1 and 2 h of consuming the juiceblend (Jensen et al., 2008). In 2011, a pilot study was performed toevaluate the effect of the juice blend on individuals with reducedrange of motion (ROM) due to pain (Jensen et al., 2011). Thestudy suggested that the juice blend increased anti-oxidant lev-els in serum (using the CAP-e assay) and this was correlatedwith improved ROM and reduced pain. The authors state thatwhile the results look promising, the significant association amongincreased anti-oxidant status, improved ROM, and pain reduc-tion warrants further study (Jensen et al., 2011). Even if in vitrosimulators suffer from the absence of a complete physiologicalenvironment, they are still valuable to study the intestinal pro-cesses in the gut itself without ethical constraints (Bolca et al.,2013).

Whole food, native compounds, and synergistic effectIt is important to note that the observed health benefit of phyto-chemicals may not necessarily occur due to the native form thatis found in food (Neilson and Ferruzzi, 2012). This is becauseof the various metabolic processes that occur after absorption.These metabolic processes that are performed by the digestiveenzymes and the gut microflora, breakdown the phytochemi-cals into simpler compounds and alter the functional groups ofthe phytochemical. Therefore the metabolites may actually be theactive compound responsible for the biological activity. However,many studies measure the biological activity of the native phy-tochemical for several reasons: (1) most phytochemicals can beconverted into many metabolites which exponentially increasesthe number of metabolites that need to be measured, (2) in manysituations, the metabolites that are generated from a phytochem-ical are unknown or incomplete, (3) the activity of the nativephytochemical is better characterized than its metabolites both invivo and in vitro, and (4) the native compound serves as a markerfor all its metabolites even if not a complete one (Neilson andFerruzzi, 2012).

It is believed that the observed beneficial activities of phy-tochemicals from fruit and vegetables are more likely due toa combined effect rather than to a single compound or smallgroup of compounds (Neilson and Ferruzzi, 2012). This isbecause when looked at in isolation the individual phytochem-ical studied in clinical trials do not appear to have consistent

preventative effects (Omenn et al., 1996; Stephens et al., 1996;Yusuf et al., 2000). The isolated compound either loses its bioac-tivity or may not behave the same way compared to when it isin whole foods. Several studies have shown that the risk of can-cer is inversely linked to eating green and yellow vegetables andfruit. B-carotene, which is present in abundance in these fruitsand vegetables, was therefore extensively studied as a possiblecancer-preventative agent. However, the result from several clin-ical studies were inconsistent (Greenberg et al., 1990; Hennekenset al., 1996; Omenn et al., 1996). In one study, the incidence ofskin cancer was unchanged in patients receiving a b-carotenesupplement (Hennekens et al., 1996). In the Heart Outcomes Pre-vention Evaluation (HOPE) study, patients at a high risk forCVD were given vitamin E supplement or placebo (Jialal et al.,2000). No difference was found in CVD mortality (Jialal et al.,2000).

Other studies have also reported on the negative impact ofanti-oxidant supplements. A systemic review in 2012 assessedthe effect of anti-oxidant supplements on mortality and healthcompared to placebo or no intervention (Bjelakovic et al., 2012).They analyzed 78 trials and concluded that there was no evidenceof benefit from consuming anti-oxidant supplements. Moreover,they found that consumption of b-carotene, vitamin E and highconcentrations of vitamin A may be harmful and increase riskof mortality (Bjelakovic et al., 2012). In another study, the asso-ciation between lung cancer and b-carotene was investigated insmokers (Omenn et al., 1996). Smokers gained no benefit fromthe supplement and the authors suggested that there may in facthave been a significant increase in lung cancer and mortality(Omenn et al., 1996).

There are thousands of phytochemicals present in whole foodswhich differ in their molecular size, polarity, and solubility (Liu,2012). These properties may affect their bioavailability and dis-tribution on different macromolecules, subcellular organelles,cells, organs, and tissues (Liu, 2012). It is thus more likelythat phytochemicals work synergistically to produce their ther-apeutic effect. A synergistic therapeutic effect is defined as astronger effect by the combination of two or more compoundscompared to individual compounds at equal concentrations(Yang and Liu, 2009).

Evidence for a synergistic therapeutic effect was seen in applestudies. A study looked at the effect of phytochemicals extractedfrom whole apple on tumor cell growth in vitro (Eberhardtet al., 2000). They found that whole apple extracts inhibitedcolon cancer proliferation in a dose-dependent manner withextracts equivalent to 0–50 mg/ml of whole apple wet weight.The phytochemicals in apples with peel exhibited a strongereffect compared to apple without peel (Eberhardt et al., 2000).Another study built on this information by performing an ani-mal study (Liu et al., 2005). They demonstrated that apple extractsprevented mammary cancer in rats in a dose-dependent man-ner comparable to human consumption of 1, 3, and 6 applesa day (Liu et al., 2005). More recently, a study examined thepotential additive, synergistic or antagonistic interaction amongapple phytochemicals (Yang and Liu, 2009). The results sug-gested that apple phytochemicals in combination with quercetin3-beta-D-glucoside (Q3G) possesses a synergistic effect against





MCF-7 human breast cancer cell proliferation (Yang and Liu,2009).

NUTRIENT MODULATION IN AUTOPHAGY AND BACTERIALSENSINGIt is emerging that nutrients have the ability to modify vari-ous cellular processes in particular autophagy (Marion-Letellieret al., 2013). Inducing autophagy through the administration ofdifferent nutrients may be beneficial for intestinal inflammation.

Many recent studies have reported the interaction betweenautophagy and dietary factors. This includes the amino acids argi-nine (arg), glutamine (gln), and leucine (leu) which play a crucialrole in intestinal growth, integrity, and function through cellularmechanisms (Rhoads and Wu, 2009). It is becoming clear thatmTOR signaling plays a part in modulating amino acid intesti-nal homeostasis (Goberdhan et al., 2009). Studies have reportedthat arg, gln, and leu regulate the mTOR pathway (Goberdhanet al., 2009). Arg has been shown to upregulate phosphorylationof S6K, a downstream effector of mTOR (Ban et al., 2004). Glninduces autophagy through the mTOR and p38 MAPK pathways(Sakiyama et al., 2009).

Flavonoids from diet, such as dihydrocapsaicin (DHC),quercetin, MK615, and soyasaponins, induce autophagy inthe intestine; however, the mechanism of action is stillundetermined (Marion-Letellier et al., 2013). The polyphe-nol quercetin was reported to induce autophagy in Caco-H2intestinal cell line with oncogenic Ras activity that resultedin preferential reduction of the Ras protein (Psahoulia et al.,2007). Saponins derived from soy bean were shown to sup-press HCT15 colon cancer cell proliferation through S-phasecell-cycle delay, and can induce macroautophagy suggestingautophagic cell death (Ellington et al., 2005). Incubation withan extract from Japanese apricot, MK615 resulted in an induc-tion of autophagy in the colon cancer cell line (Mori et al.,2007).

Peroxisome proliferator-activated receptor gamma (PPARγ)which is important in the regulation of inflammation is alsothought to regulate autophagy (Jiang et al., 2010). Polyunsaturatedfatty acids (PUFAs) and resveratrol have been shown to inducePPARγ which is highly active in the colon (Marion-Letellier et al.,2009). It has been shown that fatty acids such as docosahexaenoicacid (DHA) may be potent inducers of autophagy through PPARγ

in intestinal cells (Marion-Letellier et al., 2009).A study reported that the stimulation of autophagy by treat-

ment with vitamin D significantly enhanced the anti-microbialresponse against M. tuberculosis in human macrophages. Thiseffect seemed to be dependent on cathelicidin, a peptide that isactivated by vitamin D and enhances co-localization of bacterialphagosomes with autophagosomes (Yuk et al., 2009).

In the Department of Nutrition at the University of Auckland,our 6-week intervention study assessed the effect of a Mediter-ranean diet on inflammation (Ellett et al., 2013). During the study,blood samples were taken at the beginning and the end of the trial.CRP levels were measured as a marker of inflammation and geneexpression was measured using gene arrays. At the end of the6 weeks, CRP levels decreased and a significant change in geneexpression was observed. The change in gene expression included

TLR4 and TLR2 indicating that the TLR pathway is modulated bychanges in diet.

It is possible that chemical antagonists of NOD1 and NOD2could have a therapeutic application for diseases where dampen-ing the inflammatory response would be beneficial (Correa et al.,2012). A study has reported that certain arene-Cr(CO)3 complexesdecrease inflammatory responses and reduce NOD2-mediatedinflammatory pathways (Bielig et al., 2010). These compoundsseem to be specific for NOD2 but not TLRs or TNFα receptors(Bielig et al., 2010).

The studies highlighted here only provide a mere glimpse onthe potential of using dietary intervention to modify and primedifferent physiological processes including immunity. The inter-action between diet and the internal environment is not a newconcept. However, understanding and manipulating this interac-tion at a molecular level to gain conclusive benefit remains anambitious task due to the interdisciplinary nature of this subject.The bacterial sensing machinery was the focus of this review as itoffers a good biological process to study as they are important insensing and responding to the external environment. Nonethelessthere are other pathways that may be more relevant to a particulardisease or condition and would also be worth studying. It is likelythat understanding these pathways further and how diet can inter-act with them will contribute to developing personalized nutritionto manage disease.

CONCLUSIONIn this review, we introduced some of the main PRRs andautophagy and how they function. Additionally we revieweddietary phytochemicals which are believed to be associated withhealth and wellbeing. Dietary interactions with the host biologicalprocesses for therapeutic purposes have been the subject of greatinterest and thousands of studies and clinical trials. This reviewwas an attempt to lay down the foundations of what is alreadyknown from literature in order to help develop personalizednutrition further for better management of disease.

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Conflict of Interest Statement: The authors declare that the research was conductedin the absence of any commercial or financial relationships that could be construedas a potential conflict of interest.

Received: 17 December 2013; accepted: 13 March 2014; published online: 04 April2014.Citation: Ahmed Nasef N, Mehta S and Ferguson LR (2014) Dietary interactions withthe bacterial sensing machinery in the intestine: the plant polyphenol case. Front. Genet.5:64. doi: 10.3389/fgene.2014.00064This article was submitted to Nutrigenomics, a section of the journal Frontiers inGenetics.Copyright © 2014 Ahmed Nasef, Mehta and Ferguson. This is an open-access articledistributed under the terms of the Creative Commons Attribution License (CC BY). Theuse, distribution or reproduction in other forums is permitted, provided the originalauthor(s) or licensor are credited and that the original publication in this journal is cited,in accordance with accepted academic practice. No use, distribution or reproduction ispermitted which does not comply with these terms.


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